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1.
Heterogeneous postprandial lipoprotein responses in the metabolic syndrome, and response to fenofibrate therapy.
Rosenson, RS, Helenowski, IB, Tangney, CC
Cardiovascular drugs and therapy. 2010;(5-6):439-47
Abstract
BACKGROUND Hypertriglyceridemia subjects with metabolic syndrome exhibit variable postprandial triglyceride responses. We investigate the effects of fenofibrate therapy on postprandial triglyceride-containing lipoproteins in subjects with early (3.5 h) versus late (8 h) postprandial triglyceride responses. METHODS Fifty-five subjects with fasting hypertriglyceridemia (≥1.7 mmol/L (150 mg/ dL) and <5.8 mmol/L (500 mg/dL)) and ≥2 Adult Treatment Panel III criteria of the metabolic syndrome were randomized to daily fenofibrate (160 mg/d) or placebo for 12 weeks in a double-blind controlled clinical trial. A standardized fat load (50 g/m(2)) was given orally after a 12 h fast. Blood specimens were obtained at 0 h (fasting), 3.5 h, and 8 h after the test meal. Analysis is confined to the 53 subjects with clearly identifiable early or late triglyceride peaks prior to therapy. RESULTS Fenofibrate was more effective in late peakers (n = 8) when compared to early peakers (n = 15) with respect to reducing postprandial triglyceride concentrations (-67% vs. -34%, p = 0.0024) and large VLDL (-76% vs. -31%, p = 0.0016), and increasing total HDL particles (20% vs. 11%, p = 0.008) and large HDL particles (185% vs. 88%, p = 0.003). On fenofibrate therapy, 100% of those initially designated as late peakers were reclassified as early peakers; 47% of late peakers assigned to placebo were reclassified as early peakers. CONCLUSIONS Late postprandial triglyceride responders have attenuated clearance of large VLDL particles, but they were more responsive to fenofibrate.
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2.
[Combined antihypertensive and antilipemic therapy as one of the pillars in the poly-pharmacologic preventive strategy for patients with high cardiovascular risk].
Kékes, E
Orvosi hetilap. 2008;(39):1827-37
Abstract
Hypertension is a highly prevalent disease and a strong risk factor for cardiovascular disease in industrialized countries in Europe and North America. About 40-50% of hypertensive patients have some other cardiovascular risk factors as smoking, dyslipidemia, glucose intolerance, metabolic syndrome and diabetes. The realization of optimal therapy of these patients is a difficult task, and reaching target blood pressure values is almost impossible by monotherapy. It was realized that the simultaneous normalization of blood pressure and that of abnormal lipid profile with 2-3 or more drugs have great importance for preventing atherosclerotic complications.We started an open-formed study with about 1000 hypertensive patients complicated with dyslipidemia, visceral obesity, metabolic syndrome and diabetes type 2. The base of our therapeutic strategy was a typical poly-pharmacologic treatment with ACE inhibitor (lisinopril), calcium antagonist (amlodipine), statin (atorvastatin) and antiplatelet therapy (if it was necessary).
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3.
Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug Project).
Canner, PL, Furberg, CD, McGovern, ME
The American journal of cardiology. 2006;(4):477-9
Abstract
This post hoc analysis from the Coronary Drug Project (CDP) evaluated the effects of niacin monotherapy on clinical outcomes in patients with and without the metabolic syndrome (MS). The CDP was a randomized, placebo-controlled clinical trial of lipid-modifying agents in men with previous myocardial infarction (MI). Of the 5 drug regimens, only niacin significantly decreased definite recurrent nonfatal MI at 6 years and total mortality at a 15-year follow-up. Patients treated with niacin (n = 1,119) and placebo (n = 2,787) were grouped according to the presence or absence of the MS at baseline. The MS was defined on the basis of meeting > or =3 of 5 criteria from the current National Cholesterol Education Program guidelines in a small subgroup of patients with high-density lipoprotein cholesterol determinations at baseline and on the basis of > or =3 of 4 criteria in the total population, excluding the high-density lipoprotein cholesterol criterion. Niacin decreased the occurrence of 6-year MI and 15-year total mortality similarly among patients with or without the MS. For example, in the total population, 15-year total mortality rates were 60% and 64% (hazard ratio 0.86) in patients with the MS treated with niacin and placebo, respectively, and 50% and 57% (hazard ratio 0.86) in those without the MS (Z for interaction = 0.06, indicating homogeneity of the treatment effect across groups). In conclusion, these results support the use of niacin in postinfarction patients with and without the MS.
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4.
Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia.
Koh, KK, Han, SH, Quon, MJ, Yeal Ahn, J, Shin, EK
Diabetes care. 2005;(6):1419-24
Abstract
OBJECTIVE Improvement in endothelial function is predicted to improve insulin sensitivity, and this may be one mechanism by which fenofibrate decreases the incidence of coronary heart disease. We hypothesize fenofibrate improves endothelial function by enhancing insulin sensitivity. RESEARCH DESIGN AND METHODS We administered placebo or fenofibrate 200 mg daily for 8 weeks to 46 patients with primary hypertriglyceridemia (24 had metabolic syndrome). This study was randomized, double blind, placebo controlled, and crossover in design. RESULTS Compared with placebo, fenofibrate decreased total cholesterol, non-HDL cholesterol, apolipoprotein B, and triglycerides and increased HDL cholesterol and apolipoprotein A-I (all P < 0.001) while tending to decrease LDL cholesterol (P = 0.069). Fenofibrate significantly improved percent flow-mediated dilator response to hyperemia by 48 +/- 5% (P < 0.001) and lowered plasma levels of high-sensitivity C-reactive protein (hsCRP) relative to baseline measurements from 0.80 to 0.70 mg/l (P = 0.001) and fibrinogen levels by 16 +/- 3% (P < 0.001). Compared with placebo, fenofibrate therapy significantly increased plasma levels of adiponectin by 14 +/- 5% (P = 0.008) and increased insulin sensitivity (assessed by quantitative insulin sensitivity check index [QUICKI]) by 6 +/- 2% (P = 0.048). There were significant correlations between percent changes in adiponectin levels and percent changes in flow-mediated dilation (r = 0.401, P = 0.006), hsCRP (r = -0.443, P = 0.002), or QUICKI (r = 0.292, P = 0.049). Multivariate regression analysis showed that only changes in adiponectin levels persisted as an independent predictor of changes in flow-mediated dilation (r = 0.504, P = 0.013). Overall, we observed similar results in 24 patients with metabolic syndrome. CONCLUSIONS Fenofibrate therapy significantly improved percent flow-mediated dilator response to hyperemia, reduced inflammation marker levels, increased adiponectin levels, and improved insulin sensitivity in hypertriglyceridemic or metabolic syndrome patients.
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5.
Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome.
Watts, GF, Barrett, PH, Ji, J, Serone, AP, Chan, DC, Croft, KD, Loehrer, F, Johnson, AG
Diabetes. 2003;(3):803-11
Abstract
The metabolic syndrome is characterized by insulin resistance and abnormal apolipoprotein AI (apoAI) and apolipoprotein B-100 (apoB) metabolism that may collectively accelerate atherosclerosis. The effects of atorvastatin (40 mg/day) and micronised fenofibrate (200 mg/day) on the kinetics of apoAI and apoB were investigated in a controlled cross-over trial of 11 dyslipidemic men with the metabolic syndrome. ApoAI and apoB kinetics were studied following intravenous d(3)-leucine administration using gas-chromatography mass spectrometry with data analyzed by compartmental modeling. Compared with placebo, atorvastatin significantly decreased (P < 0.001) plasma concentrations of cholesterol, triglyceride, LDL cholesterol, VLDL apoB, intermediate-density lipoprotein (IDL) apoB, and LDL apoB. Fenofibrate significantly decreased (P < 0.001) plasma triglyceride and VLDL apoB and elevated HDL(2) cholesterol (P < 0.001), HDL(3) cholesterol (P < 0.01), apoAI (P = 0.01), and apoAII (P < 0.001) concentrations, but it did not significantly alter LDL cholesterol. Atorvastatin significantly increased (P < 0.002) the fractional catabolic rate (FCR) of VLDL apoB, IDL apoB, and LDL apoB but did not affect the production of apoB in any lipoprotein fraction or in the turnover of apoAI. Fenofibrate significantly increased (P < 0.01) the FCR of VLDL, IDL, and LDL apoB but did not affect the production of VLDL apoB. Relative to placebo and atorvastatin, fenofibrate significantly increased the production (P < 0.001) and FCR (P = 0.016) of apoAI. Both agents significantly lowered plasma triglycerides and apoCIII concentrations, but only atorvastatin significantly lowered (P < 0.001) plasma cholesteryl ester transfer protein activity. Neither treatment altered insulin resistance. In conclusion, these differential effects of atorvastatin and fenofibrate on apoAI and apoB kinetics support the use of combination therapy for optimally regulating dyslipoproteinemia in the metabolic syndrome.
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6.
Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome.
Vega, GL, Ma, PT, Cater, NB, Filipchuk, N, Meguro, S, Garcia-Garcia, AB, Grundy, SM
The American journal of cardiology. 2003;(8):956-60
Abstract
Combined hyperlipidemia predisposes subjects to coronary heart disease. Two lipid abnormalities--increased cholesterol and atherogenic dyslipidemia--are potential targets of lipid-lowering therapy. Successful management of both may require combined drug therapy. Statins are effective low-density lipoprotein (LDL) cholesterol-lowering drugs. For atherogenic dyslipidemia (high triglycerides, small LDL, and low high-density lipoprotein [HDL]), fibrates are potentially beneficial. The present study was designed to examine the safety and efficacy of a combination of low-dose simvastatin and fenofibrate in the treatment of combined hyperlipidemia. It was a randomized, placebo-controlled trial with a crossover design. Three randomized phases were employed (double placebo, simvastatin 10 mg/day and placebo, and simvastatin 10 mg/day plus fenofibrate 200 mg/day). Each phase lasted 3 months, and in the last week of each phase, measurements were made of plasma lipids, lipoprotein cholesterol, plasma apolipoproteins B, C-II, and C-III and LDL speciation on 3 consecutive days. Simvastatin therapy decreased total cholesterol by 27%, non-HDL cholesterol by 30%, total apolipoprotein B by 31%, very low-density lipoprotein (VLDL) + intermediate-density lipoprotein (IDL) cholesterol by 37%, VLDL + IDL apolipoprotein B by 14%, LDL cholesterol by 28%, and LDL apolipoprotein B by 21%. The addition of fenofibrate caused an additional decrease in VLDL + IDL cholesterol and VLDL + IDL apolipoprotein B by 36% and 32%, respectively. Simvastatin alone caused a small increase in the ratio of large-to-small LDL, whereas the addition of fenofibrate to simvastatin therapy caused a marked increase in the ratio of large-to-small LDL species. Simvastatin alone produced a small (6%) and insignificant increase in HDL cholesterol concentrations. When fenofibrate was added to simvastatin therapy, HDL cholesterol increased significantly by 23%. No significant side effects were observed with either simvastatin alone or with combined drug therapy. Therefore, a combination of simvastatin 10 mg/day and fenofibrate 200 mg/day appears to be effective and safe for the treatment of atherogenic dyslipidemia in combined hyperlipidemia.
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7.
Free fatty acid metabolism during fenofibrate treatment of the metabolic syndrome.
Vega, GL, Cater, NB, Hadizadeh, DR, Meguro, S, Grundy, SM
Clinical pharmacology and therapeutics. 2003;(3):236-44
Abstract
OBJECTIVE Our objective was to determine whether fenofibrate modifies the metabolism of nonesterified (free) fatty acids as a component of its triglyceride-lowering action in male patients with the metabolic syndrome. DESIGN In a placebo-controlled trial lasting 16 weeks, patients were randomly assigned to fenofibrate (200 mg/d) or placebo for 8 weeks. They were then crossed over to placebo or treatment with fenofibrate for another 8 weeks. METHODS Thirteen adult men had clinical characteristics of the metabolic syndrome that included atherogenic dyslipidemia, hypertension, elevated fasting glucose levels, or central obesity or a combination of these. They had measurements of plasma lipid and lipoprotein levels, postheparin lipase activities, and fasting concentrations and turnover rates of nonesterified fatty acids, as well as oral glucose tolerance testing with insulin and nonesterified fatty acid measurements. Levels of apolipoprotein C-II, C-III, and B were also measured, along with levels of low-density lipoprotein cholesterol in lipoprotein species. RESULTS Fenofibrate therapy did not change plasma concentrations and turnover rates of nonesterified fatty acids. For fasting nonesterified fatty acids, the values (mean +/- SD) for placebo versus fenofibrate were 446 +/- 31 micromol/L versus 493 +/- 71 micromol/L, respectively (not significant); nonesterified fatty acid turnover rates were 336 +/- 36 micromol/min versus 334 +/- 42 micromol/min for placebo versus fenofibrate, respectively. Moreover, no changes were noted in fasting or postprandial levels of plasma glucose and insulin. Despite this lack of change, fenofibrate therapy reduced the plasma levels of triglyceride by 30% (305 +/- 143 mg/dL versus 206 +/- 90 mg/dL for placebo versus fenofibrate, respectively; P <.045), with a similar reduction in cholesterol levels of triglyceride-rich lipoproteins. Large low-density lipoprotein species were increased and small low-density lipoprotein species were decreased by fenofibrate therapy. Levels of apolipoprotein C-III were reduced significantly (P <.03), as were ratios of postheparin hepatic lipase to lipoprotein lipase (P <.05). CONCLUSION Fenofibrate therapy markedly reduced plasma triglyceride levels. However, it did not lower concentrations or turnover rates of nonesterified fatty acids, nor did it change glucose or insulin responses to an oral glucose challenge. These findings indicate that fenofibrate modifies fatty acid metabolism either in the liver or in triglyceride-rich lipoproteins but not in adipose tissue. Multiple mechanisms are likely involved as a consequence of the action of fenofibrate to activate peroxisomal-proliferator-activated receptor alpha.
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8.
Cholesterol synthesis and absorption in coronary patients with lipid triad and isolated high LDL cholesterol in a 4S subgroup.
Miettinen, TA, Gylling, H
Atherosclerosis. 2003;(2):343-9
Abstract
We assumed that assaying serum cholesterol precursors (synthesis markers) and plant sterols and cholestanol (absorption markers of cholesterol) reveals differences in cholesterol synthesis and absorption in the Finnish 4S subgroup divided in high triglyceride-low HDL cholesterol (lipid triad=HTG) and isolated high LDL cholesterol (ILDL) groups. Serum squalene and non-cholesterol sterol ratios to cholesterol were measured with gas-liquid chromatography at baseline, 6 weeks, 1 year, and 5 years on simvastatin. Patients with HTG (n=135) exhibited features of metabolic syndrome and, in spite of similar serum total and LDL cholesterol levels, ratios of synthesis markers were higher and those of absorption markers lower than in ILDL (n=133). The latter patients accumulated to a subgroup shown earlier to be clinical non-responders to simvastatin in 4S. Serum cholesterol reduction by simvastatin only tended to be higher in HTG than ILDL. The synthesis marker ratios were markedly reduced, and more effectively in HTG than ILDL, while the absorption marker ratios were increased, and for plant sterols more in ILDL than HTG. In conclusion, HTG is associated with high synthesis and low absorption of cholesterol, these events being opposite in ILDL. Synthesis is more effectively reduced by simvastatin in HTG than ILDL in spite of similar reduction in serum cholesterol. Patients defined by highest baseline absorption marker ratios in ILDL group are poor coronary event-reducers on regular simvastatin treatment.
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9.
Gemfibrozil improves insulin sensitivity and flow-mediated vasodilatation in type 2 diabetic patients.
Avogaro, A, Miola, M, Favaro, A, Gottardo, L, Pacini, G, Manzato, E, Zambon, S, Sacerdoti, D, de Kreutzenberg, S, Piliego, T, et al
European journal of clinical investigation. 2001;(7):603-9
Abstract
BACKGROUND Endothelial dysfunction is an early feature of atherosclerosis. The relationship between insulin action and hypertriglyceridaemia on endothelial function is still debated. MATERIALS AND METHODS This study was designed to determine the effect of a 3 month treatment with Gemfibrozil (GF) on flow-mediated vasodilatation and insulin sensitivity. Ten type 2 diabetic patients were randomised in crossover, double blind fashion, either to GF, 600 mg b.i.d. or placebo, for 12 weeks. Lipid profile, low-density lipoprotein (LDL) distribution and flotation properties, insulin action and flow-mediated vasodilatation (FMD) by brachial artery ultrasound, were assessed. RESULTS GF decreased serum triglyceride (TG) concentration with an absolute difference of 1.79 +/- 1.28 mmol L-1 (P < 0.0016) between active treatment and placebo, and significantly increased serum high-density lipoprotein (HDL) cholesterol (P = 0.0233). No differences were observed in total, intermediate-density lipoproteins (IDL), LDL cholesterol concentration and LDL peak buoyancy between treatments. GF also improved SI, an index of insulin action (P = 0.005). The FMD was 7 +/- 3% in the baseline condition, 7 +/- 2% during placebo and 14 +/- 3% after GF (P < 0.006). CONCLUSIONS GF treatment improves both insulin action and flow-mediated vasodilatation in type 2 diabetic patients. The reduction of TG concentration allows the simultaneous correction of two important components of the metabolic syndrome.